RF1NS132784

Biophysical mechanisms of cortical microstimulation - Direct local electrical stimulation (DLES) is an increasingly important therapeutic tool for treating brain disorders such as Parkinson's, epilepsy, and OCD. There is considerable disagreement, however, as to how neural stimulation, especially at the scale of neurons, affects human brain function.

This lack of understanding hampers the design and implementation of more effective stimulation approaches, particularly in the cortex. To deliver on the precise, inclusive, and effective therapeutic promise of DLES, a more mechanistic understanding of the biophysics of cortical stimulation is required.

This project combines single-cell electrophysiology in both human and mouse cortex, both ex-vivo and in vivo, with pharmacology, optical physiology, and sophisticated computational modeling to identify the mechanisms underlying electrical stimulation.

In a truly translational approach, these multiple research angles will allow us to test in-depth mechanistic hypotheses in the mouse and whether these results hold true in the human. We will test the hypothesis that DLES induces a dynamic sequence of excitatory (E) neuron output countered by subsequent inhibitory (I) neuron.

We will evaluate stimulation intensity, frequency, phase, distance, and species as key parameters in modulating the timing and strength of this E-I dynamic sequence. These data on neuronal dynamics will be leveraged into actionable knowledge through an integrate-and-fire based recurrent neuronal network model which we will use to predict cortical responses to novel stimuli and develop specific stimulation patterns to evoke desired neural outputs.

Specifically, we will identify the biophysical mechanisms by which DLES recruits different neuronal populations in acute brain slices of human and mouse cortex using whole-cell electrophysiology and pharmacology (Aim 1). We will then characterize neuron and population responses to DLES in vivo, using Neuropixels probes in awake human and mouse cortex, complemented by optical recordings in the awake mouse (Aim 2).

This extensive and detailed dataset will be used to refine and validate a trainable neural network model we have developed to assess stimulation effects on E and I cell types (Aim 3). The model will be the testing ground to develop specific patterns of stimulation based on desired outputs such as targeting either E or I cells.

The model will also be used to test novel input stimuli including amplitude and frequency ramps, chirps, and step functions to predict neural responses. Testing these model-predicted outputs, or responses, will then be carried out through further ex- and in-vivo physiology.

Not only will we connect dynamics of a primary model system to activity in the human brain, but this work will also provide a unique route toward predictable modulation of activity in individual neurons and local circuits to design tailored neuromodulation therapies.

Our multi-scale analyses of the neural mechanisms of electrical stimulation will catalyze novel, targeted, and mechanistically driven therapeutic approaches that could revolutionize stimulation-based treatment for memory disorders, depression, stroke recovery, and a host of other neuropsychiatric ailments.

The General Hospital Corporation

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.279 - Drug Abuse and Addiction Research Programs

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

National Institute on Drug Abuse (NIDA) [HHS - NIH]

Boston, Massachusetts 021142621 United States

Single Zip Code

BRAIN Initiative: Biology and Biophysics of Neural Stimulation and Recording Technologies (R01 Clinical Trials Optional) (RFA-NS-20-006)

Amendment Since initial award the total obligations have increased 54% from $2,180,597 to $3,360,184.